Generally, a coating of a pharmaceutical product consists of one or more films and each film consists of one or more layers. Below, “coating” is used as a comprehensive expression encompassing everything from an individual layer to a combination of several different films. Each film is the result of a single coating step, generally performed in a coating vessel, where for instance layers of the film are built up. The coating process takes place either in a fluidized bed wherein particles, so-called nuclei, arc sprayed with a specific coating liquid, or by passing the particles through a spray dust of said liquid. Several other generally used coating techniques are known in the prior art, such as melting, aggregation etc. The total process of manufacturing a complete coating may involve a plurality of such coating steps. However, the process may as well be sequential, whereby the whole process represents a continuous flow.
Pharmaceutical products are coated for several reasons. A protective coating normally protects the active ingredients from possible negative influences from the environment, such as for example light and moisture but also temperature and vibrations. By applying such a coating, the active substance is protected during storage and transport. A coating could also be applied to make the product easier to swallow, to provide it with a pleasant taste or for identification of the product. Further, coatings are applied which perform a pharmaceutical function such as conferring enteric and or controlled release. The purpose of a functional coating is to provide a pharmaceutical preparation or formulation with desired properties to enable the transport of the active pharmaceutical substance through the digestive system to the region where it is to be released and/or absorbed. A desired concentration profile over time of the active substance in the body may be obtained by such a controlled course of release. An enteric coating is used to protect the product from disintegration in the acid environment of the stomach. Moreover, it is important that the desired functionalities are constant over time, i.e. during storage. By controlling the quality of the coating, the desired functionalities of the final product may also be controlled.
There are strict requirements from the different Registration Authorities on pharmaceutical products. These requirements will put high demands on the quality of the coating and require that the complex properties of the coating will be kept within narrow limits. In order to meet these demands, there is a need for accurate control of the coating process.
The quality of the coating depends on physical and/or chemical properties of the coating, such as chemical composition, local inhomogeneities, physical and chemical homogeneity, density, mechanical properties, static parameters, modulus, tensile strength, elongation at break, compression, ductility, viscoelastic parameters, morphology, macro-and microscopic properties, amorphous and/or crystallinity, permeability, porosity, aggregation, wettability, degree of coalescence/maturity, stability and ability to resist chemical and/or physical degradation. There are also other properties not listed above. The quality of the coating affects to a great extent the release properties and has a significant impact on the storage stability. In order to keep the quality of the coating within the desired narrow limits it is necessary to control the manufacturing process of the coating accurately.
In an industrial plant for coating pharmaceutical products, selected process parameters are monitored and controlled to achieve a desired quality of the end product. Such process parameters are generally global and could include, for example, the pressure in the coating vessel, the flow rate and temperature of gas and coating liquid supplied to the coating vessel, etc. However, the influence of such global process parameters of the coating process, and ultimately on the coating properties of the end product, is known only from experience in a specific plant. Thus, a processing scheme is developed for each specific plant by extensive testing. When, for example, the size or shape of the coating vessel is changed during scaling up of the process, the local environment of the particles may be altered. This calls for time-consuming measurements and adjustments in order to regain the same coating properties of the end product.
There is also a need to improve existing manufacturing processes as well as to improve existing plants. Today, this is a laborious task since the influence of any change in the process scheme or the plant design on the end product has to be investigated by extensive testing, often in full scale. The same applies to the development of new products, for example when a new type of particle or coating liquid should be used.
An attempt to fulfil the above-identified needs is disclosed in the article “Fluidized bed spray granulation, investigation of the coating process on a single sphere” by K. C. Link and E.-U. Schlünder, published in Chemical Engineering and Processing, No. 36, 1997. A laboratory-scale apparatus is designed for analysis of a single particle, in order to investigate the fundamental physical mechanisms that lead to particle growth by layering. In this apparatus, a single aluminum sphere is made to levitate on a fluidizing air flow which is supplied by a capillary tube. Thereby, the sphere is freely and rotatably suspended at a stable location in a coating vessel. An ultrasonic nozzle arranged above this stable location is intermittently activated to generate a spray dust of coating liquid that falls down onto the sphere and forms a coating thereon. This type of nozzle generates a spray of droplets, the velocity of which is adjusted by means of a separate air flow through the nozzle. The apparatus is used for investigating the influence of different parameters, such as droplet velocity, temperature of fluidizing air, drying time, and type of coating liquid, on the thickness and morphology of the resulting coating. A rough measurement value of the overall thickness of the coating is obtained by weighing the sphere before and after the actual coating process and determining the difference in weight. The morphology of the coating is qualitatively examined by arranging the sphere, once coated, in a scanning-electron-microscope (SEM). For both of these measurements, the sphere must be removed from the apparatus for analysis. The apparatus also includes a lamp for illumination of the sphere and a video camera for continuous and qualitative observation of the continuous of the sphere during the coating process.
One drawback of this prior-art apparatus resides in the difficulty to make quantitative, time-resolved measurements of coating properties. After a specific time period, the coating process must be interrupted for analysis of the coating on tile sphere, whereupon a new and non-coated sphere must be subjected to a new coating process for a longer time period, and so on. In this approach, the formation of a coherent time series of measurement data requires that identical conditions are maintained in the environment of each sphere. Thus, the coating process must be repeated in exactly the same manner for each sphere. This is difficult. For example, any small variations in the masses of the aluminum spheres will necessitate an adjustment in the flow rate of the fluidizing air, to maintain each sphere at the same location in the vessel. Such a change in now rate will also change the environment of the sphere during the coating process, thereby making it difficult to compile the measurement data from several consecutive measurements into a coherent time series.
A further drawback of this known apparatus is that only a few properties of the coating, i.e. average thickness and surface morphology, can be measured.
Another drawback is that the course of a coating process can only be studied on standardized spheres, so that the coating process can be repeated in exactly the same manner for each sphere. However, the coating process is believed to be highly dependent on the properties of the particle itself, such as the size, density, porosity and shape of the particle. Thus, it may be difficult, or even impossible, to draw any conclusions lot a realistic particle from experiments made in the known apparatus.